Cocaine abuse continues to play a major role in the rapid spread of acquired immune deficiency syndrome and drug-resistant tuberculosis from needle sharing, sex for drugs and related activities in shooting galleries, crack houses, and similar establishments. The devastating effect on public health worldwide of the current cocaine epidemic has prompted many studies to understand the mechanism of cocaine's action. Numerous parallel studies have been aimed at the development of safe and effective medications (which are presently unknown) for the treatment of cocaine addiction. One of our approaches to the development of medications for the treatment of cocaine dependence involves the development of high-affinity, slowly dissociating, low-intrinsic activity cocaine receptor agonists. We showed that the disubstituted piperazine GBR 12909 decreases the cocaine-maintained responding without decreasing normal food-maintained responding in rhesus monkeys. We have now deveolped DLB 583, an ultra long acting analog of GBR 12909 which decreased cocaine self-administration more than 80% without affecting control (food-maintained) responding for almost 30 days after a single dose. We have now synthesized and evaluated a new series of heteroaromatic GBR 12909 analogs as dopamine transporter (DAT) ligands. Analogs in which the benzene ring in the phenylpropyl side chain of the GBR molecule had been replaced with a thiophene, furan, or pyridine ring, exhibited high affinity and selectivity for the DAT vs. serotonin transporter (SERT) and stimulated locomotor activity in rats in a manner similar to the parent compound. In cocaine and food self-administration studies in rhesus monkeys, both thiophene-containing and pyridine-containing derivatives displayed potency comparable to the parent molecule in decreasing the cocaine-maintained responding at the doses tested (0.3, 1.7, and 3 mg/kg). Among the bicyclic fused-ring congeners an indole-containing analog showed the greatest affinity for binding to the DAT, with IC50 = 0.7 nM, and a related indole-containing analog displayed the highest selectivity (over 600-fold) at this site vs. the SERT site. Overall, these results suggest that the development of a partial agonist, or a series of partial agonists of GBR-type compounds with high affinity and selectivity at the DAT is a suitable approach toward the development of potential medications for the treatment of cocaine abuse and addiction.